Abnormal or deficient hemoglobin, the major protein in red blood cells, causes severe anemia and organ damage in β-thalassemia and sickle cell anemia (β-hemoglobinopathies). HbF is another type of hemoglobin that is expressed in all humans before birth and functions well, but is silenced during infancy. When re-activated, HbF ameliorates these conditions by replacing some function of the abnormal “adult” genes with normal fetal globin protein.
At adequate levels, HbF reduces anemia in β-thalassemia and prevents many complications of sickle cell disease. PB-04 has additive activity with hydroxyurea, the primary therapy for sickle cell disease.
PB-04 was identified in a high-throughput robotic screen of approved or clinical stage drugs as a potent inducer of HbF. Activity was validated in multiple systems, including nonhuman primates and transgenic mice models predictive of human clinical responses.
PB-04 has 40 years of commercial use, solely in combination with another drug in an unrelated condition, and has never been formulated or approved as a single agent drug. This allows Phoenicia to repurpose it as a novel proprietary therapeutic for β-hemoglobin disorders without risk of substitution by an existing product.
Novel mechanism of action: PB-04 reactivates fetal hemoglobin (HbF) by suppressing 4 repressors, BCL11A, KLF1, LSD1, HDAC2. Treatment displaces the major repressor complex that silences HbF, in actively dividing erythroid cells cultured from patients and in anemic animal models.
